One of the most well-known and widely-used classes of antibacterial agents in the class known as the beta-lactam antibiotics. These compounds are characterized in that they have a nucleus consisting of a 2-azetidinone (beta-lactam) ring fused to either a thiazolidine or a dihydro-1,3-thiazine ring. When the nucleus contains a thiazolidine ring, the compounds are usually referred to generically as penicillins, whereas when the nucleus contains a dihydrothiazine ring, the compounds are referred to as cephalosporins. Typical examples of penicillins which are commonly used in clinical practice are benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), ampicillin, amoxicillin and carbenicillin; typical examples of common cephalosporins are cephalothin, cephalexin and cefazolin.
However, despite the wide use and wide acceptance of the beta-lactam antibiotics as valuable chemotherapeutic agents, they suffer from the major drawback that certain members are not active against certain microorganisms. It is thought that in many instances this resistance of a particular microorganism to a given beta-lactam antibiotic results because the microorganism produces a beta-lactamase. The latter substances are enzymes which cleave the beta-lactam ring of penicillins and cephalosporins to give products which are devoid of antibacterial activity. However, certain substances have the ability to inhibit beta-lactamases, and when a beta-lactamase inhibitor is used in combination with a penicillin or cephalosporin it can increase or enhance the antibacterial effectiveness of the penicillin or cephalosporin against certain microorganisms. It is considered that there is an enhancement of antibacterial effectiveness when the antibacterial activity of a combination of a beta-lactamase inhibiting substance and a beta-lactam antibiotic is significantly greater than the sum of the antibacterial activities of the individual components.
Thus, according to the invention, there are provided certain new chemcial compounds which are inhibitors of microbial, especially bacterial, beta-lactamases. More specifically, these new chemical compounds are 6-beta-halopenicillanic acid 1,1-dioxides, pharmaceutically-acceptable base salts thereof, i.e. physiologically acceptable salts thereof, and readily hydrolyzable esters thereof. Of the aforesaid esters, those which are readily hydrolyzable in vivo are of course preferred. Additionally, there is provided a method for enhancing the effectiveness of beta-lactam antibiotics using said new chemical compounds, and pharmaceutical compositions comprising said new chemical compounds.
U.S. Pat. No. 4,234,579 discloses the use of penicillanic acid 1,1-dioxide, and esters thereof readily hydrolyzable in vivo, as antibacterial agents and as beta-lactamase inhibitors. U.S. Pat. No. 4,180,506 discloses 6-beta-bromopenicillanic acid as an antibacterial agent and as a beta-lactamase inhibitor.
Harrison et al., Journal of the Chemical Society (London), Perkin I, 1772 (1976) disclose: (a) the oxidation of 6,6-dibromopenicillanic acid with 3-chloroperbenzoic acid, to give a mixture of the corresponding alpha- and beta-sulfoxides; (b) oxidation of methyl 6,6-dibromopenicillanate with 3-chloroperbenzoic acid to give a methyl 6,6-dibromopenicillanate 1,1-dioxide; (c) oxidation of methyl 6-alpha-chloropenicillanate with 3-chloroperbenzoic acid, to give a mixture of the corresponding alpha- and beta-sulfoxides; and (d) oxidation of methyl 6-alpha-bromopenicillanate with 3-chloroperbenzoic acid, to give a mixture of the corresponding alpha- and beta-sulfoxides.
Clayton, Journal of the Chemical Society (London), Part C, 2123 (1969) discloses inter alia: (a) 6-alpha-iodopenicillanic acid and its methyl ester; and (b) 6,6-diiodopenicillanic acid and its methyl ester.